Our research is focused on elucidating the relationship between the perturbations in glucose metabolism associated with type 1 diabetes mellitus (T1DM) and the higher prevalence of major depressive episodes in this patient population. Converging evidence associating high brain levels of glutamate (Glu) with T1DM and depression leads us to hypothesize that the link between diabetes-related glucose metabolic disorders and depression is excessive brain Glu. The overarching aim of our proposed study is to examine the effect of chronic and acute hyperglycemia in T1DM on brain Glu levels. We plan to study and characterize four subject groups: T1DM patients with (N=30) and without (N=30) current depressive symptoms, and non-diabetic subjects with (N=30) and without (N=30) current depressive symptoms (Total N=120). We will examine two brain regions: the anterior cingulate cortex (ACC), known to play an essential role in the regulation of emotions, and a control occipital cortex region. We will measure regional brain Glu concentrations using high-field (4 Tesla) localized multidimensional magnetic resonance spectroscopy (MRS), evaluate current depression symptom severity and depression history using psychiatric assessment, perform extensive medical evaluation of patients including evaluation of glycemic control (HbA1c), evaluate behavioral performance on emotional and cognitive tasks and evaluate regional cortical thickness (CT) using high-resolution MR imaging (MRI). For all subjects, MRS brain Glu will be assessed during basal normoglycemia and, for 10 subjects/group, during an acute hyperglycemic clamp (Total N=40). To control for potential confounding effects of hyperinsulinemia, brain Glu will also be assessed during a euglycemic hyperinsulinemic clamp in 10 controls (N=10). We will address five sets of primary hypotheses: 1) Basal brain glutamate will be higher in T1DM patients than non- diabetic controls and associated with high current HbA1c levels; 2) Acute hyperglycemia will increase regional brain glutamate in T1DM, and brain glutamate increments during acute hyperglycemia will be larger in T1DM patients with current depressive symptoms than in patients without; 3) Basal brain glutamate will be higher in subjects with current depressive symptoms than in subjects without, and highest in T1DM patients with current depressive symptoms; 4) Deficits in emotional processing function will be associated with high basal brain glutamate in all subjects, and will be greatest in T1DM patients with current depressive symptoms; 5) Decreases in cortical thickness will be higher in T1DM patients than non-diabetic controls and will be greatest in T1DM patients with a history of depression. This study will investigate the association of brain glutamate with depression indices, emotional and cognitive function and brain cortical structure in T1DM. The 2x2 group design and acute experiment will explore interactions between T1DM and depression for brain metabolism, function and structure. This research could lead to improved therapies targeting specific metabolic or neurotransmitter pathways to reduce or prevent depression in T1DM. PUBLIC HEALTH RELEVANCE: The emphasis of our research is to clarify the relationship between the abnormalities in glucose metabolism associated with type 1 diabetes mellitus (T1DM) and the higher frequency of major depressive episodes observed in this patient population. Because our research has shown associations between chronic high blood glucose levels in T1DM, depression, and high brain levels of the main excitatory neurotransmitter glutamate, the aim of our proposed study is to examine the effects of chronic and acute hyperglycemia in T1DM on brain glutamate levels and their relationship to depression. This research could lead to improved therapies targeting specific pathways to reduce or prevent development of depression in T1DM.